During embryonic development, the tissues of the body are formed from three major cell populations: ectoderm, mesoderm and definitive endoderm. These cell populations, also known as primary germ cell layers, are formed through a process known as gastrulation. Following gastrulation, each primary germ cell layer generates a specific set of cell populations and tissues. Mesoderm gives rise to blood cells, endothelial cells, cardiac and skeletal muscle, and adipocytes. Definitive endoderm generates liver, pancreas and lung. Ectoderm gives rise to the nervous system, skin and adrenal tissues. The process of tissue development from these germ cell layers involves multiple differentiation steps, reflecting complex molecular changes. With respect to mesoderm and its derivatives, three distinct stages have been defined. The first is the induction of mesoderm from cells within a structure known as the epiblast. The newly formed mesoderm, also known as nascent mesoderm, migrates to different positions that will be sites of future tissue development in the early embryo. This process, known as patterning, entails some molecular changes that are likely reflective of the initial stages of differentiation towards specific tissues. The final stage, known as specification, involves the generation of distinct tissues from the patterned mesodermal subpopulations.
Evidence suggests that mesoderm is induced in successive waves which represent subpopulations with distinct developmental potential. The mesoderm that is formed first migrates to the extraembryonic region and gives rise to hematopoietic and endothelial cells, whereas the next population migrates anteriorly in the developing embryo and contributes to the heart and cranial mesenchyme. These lineage relationships were defined initially through histological analysis and have been largely confirmed by cell tracing studies. With respect to hematopoietic commitment, there is now compelling evidence from studies with the ES cell differentiation model and on the mouse embryo that the earliest identifiable progenitor is a cell that also displays vascular potential, a cell that is known as the hemangioblast (Choi et al. (1998); Development 125:725-732; Huber et al. (2004) Nature 432:625-30). Analysis of this progenitor revealed that it co-expresses the mesoderm gene brachyury and the receptor tyrosine kinase Flk-1, indicating that it represents a subpopulation of mesoderm undergoing commitment to the hematopoietic and vascular lineages (Fehling et al. (2003) Development 130:4217-4227). Lineage-tracing studies have demonstrated that the heart develops from a Flk-1+ population, suggesting that a comparable multipotential cell may exist for the cardiovascular system (Ema et al. (2006) Blood 107:111-117). Analyses of ES cell differentiation cultures have provided evidence for the existence of a Flk-1+ progenitor with cardiac and endothelial potential (Yamashita et al. (2005) FASEB 19:1534-1536). Recent studies also support the existence of murine cardiovascular progenitors that may give rise to multiple cardiovascular lineages. (Kattman et al. (2006) Dev. Cell 11:723-732; Moretti et al. (2006) Cell 127:1151-1165; Wu et al. (2006) Cell 127:1137-1150). A human cardiovascular progenitor population has not heretofore been identified.